Novel arylglycinamide derivatives, method of producing said derivatives and pharmaceutical compositions containing these compounds

ABSTRACT

The invention relates to new arylglycinamide derivatives of general formula I  
                 
 
     and the pharmaceutically acceptable salts thereof, wherein R 1  and R 2  together with the N to which they are bound form a ring of the formula  
                 
 
     in which  
     R 3 , R 4 , R 5 , Ar, R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , r, s and t have the meanings given in the specification and the preparation and use thereof. The new compounds are valuable neurokinin (tachykinin) antagonists.

[0001] The invention relates to new arylglycinamide derivatives ofgeneral formula

[0002] and the pharmaceutically acceptable salts thereof, processes forpreparing them and pharmaceutical compositions containing thesecompounds. The compounds are valuable neurokinin (tachykinin)antagonists.

[0003] The abbreviations used in this specification and claims areexplained as follows: CDI Carbonyldiimidazole DCCIDicyclohexylcarbodiimide HOBt 1-Hydroxybenzotriazole THF TetrahydrofuranDMF Dimethylformamide RT Room temperature DMAP 4-DimethylaminopyridineTBTU O-Benzotriazolyl-tetramethyluronium- tetrafluoroborate

[0004] The formulae are shown in simplified form. In representing thecompounds, for example, all the CH₃-substituents are represented by ahyphen and CH is represented by, thus, for example:

[0005] The invention relates to new arylglycinamide derivatives ofgeneral formula I

[0006] or the pharmaceutically acceptable salts thereof, wherein

[0007] Ar denotes unsubstituted or mono- to penta-substituted phenyl, orunsubstituted or mono- or disubstituted naphthyl [wherein thesubstituents of the phenyl and naphthyl independently of one anotherdenote halogen (F, Cl, Br, I), (C₁₋₄)alkyl, O—(C₁₋₄)alkyl, CF₃, OCF₃ orNR¹²R¹³ (wherein R¹² and R¹³ independently of one another denote H,methyl or acetyl)] or Ar is phenyl substituted by —O—CH₂—O— or—O—(CH₂)₂—O—;

[0008] R¹ and R² together with the N to which they are bound denote aring of the formula

[0009]  wherein

[0010] r, s and t are 2 or 3;

[0011] R⁶ denotes

[0012] H,

[0013] (C₁₋₅)alkyl,

[0014] (C₃₋₅)alkenyl,

[0015] propynyl,

[0016] hydroxy(C₂₋₄)alkyl,

[0017] methoxy(C₂₋₄)alkyl,

[0018] di(C₁₋₃)alkylamino(C₂₋₄)alkyl,

[0019] amino(C₂₋₄)alkyl,

[0020] amino,

[0021] di(C₁₋₃)alkylamino,

[0022] monofluoro- to perfluoro(C₁₋₂)alkyl,

[0023] N-methylpiperidinyl,

[0024] pyridyl,

[0025] pyrimidinyl,

[0026] pyrazinyl,

[0027] pyridazinyl

[0028] or the group —CH₂—C(O)NR¹⁴R¹⁵,

[0029]  wherein

[0030] R¹⁴ is H or (C₁₋₄)alkyl and

[0031] R¹⁵ is H, (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl, hydroxy(C₂₋₄)alkyl,alkoxy(C₂₋₃)alkyl, phenyl(C₁₋₄)alkyl, or R¹⁴ and R¹⁵ together with the Nto which they are bound form a ring (1-pyrrolidinyl, piperidino,morpholino or 1-methylpiperazin-4-yl);

[0032] R⁷ has one of the definitions (a) to (d),

[0033] (a) hydroxy

[0034] (b) 4-piperidinopiperidyl,

[0035]  wherein R¹⁶ and R¹⁷ independently of one another denote

[0036] H,

[0037] (C₁₋₄)alkyl,

[0038] (C₃₋₆)cycloalkyl,

[0039] hydroxy(C₂₋₄)alkyl,

[0040] (C₁₋₃)alkoxy(C₂₋₄)alkyl,

[0041] phenyl(C₁₋₄)alkyl or

[0042] di(C₁₋₃)alkylamino(C₂₋₄)alkyl,

[0043] or if R¹⁶ is H or (C₁₋₄)alkyl,

[0044] R¹⁷ may also be —CH₂C(O)NR¹⁸R¹⁹, wherein R¹⁸ and R¹⁹ are definedas R¹⁴ and R¹⁵ hereinbefore;

[0045]  wherein R²⁰ denotes

[0046] H,

[0047] (C₁₋₄)alkyl,

[0048] (C₄₋₆)cycloalkyl or

[0049] —CH₂C(O)NR²¹R²²,

[0050] wherein R²¹ and R²² are defined as R¹⁴ and R¹⁵ hereinbefore;

[0051] R⁸ is H

[0052] R⁹ and R¹⁰ independently of each other denote (C₁₋₄)alkyl;

[0053] R¹¹ denotes

[0054] H,

[0055] (C₁₋₅)alkyl,

[0056] (C₃₋₅)alkenyl,

[0057] propynyl,

[0058] hydroxy(C₂₋₄)alkyl,

[0059] methoxy(C₂₋₃)alkyl,

[0060] di(C₁₋₃)alkylamino(C₂₋₃)alkyl,

[0061] amino(C₂₋₃)alkyl,

[0062] amino,

[0063] di(C₁₋₃)alkylamino,

[0064] monofluoro- to perfluoro(C₁₋₂)alkyl,

[0065] N-methylpiperidinyl,

[0066] pyridyl,

[0067] pyrimidinyl,

[0068] pyrazinyl,

[0069] pyridazinyl

[0070] or the group —CH₂—C(O)NR²³R²⁴,

[0071] wherein R²³ and R²⁴ are defined as R¹⁴ and R¹⁵ hereinbefore;

[0072] R³ denotes H, (C₁₋₄)alkyl, unsubstituted or mono- totrisubstituted phenyl, wherein the substituents independently of oneanother denote halogen (F, Cl, Br, I), (C₁₋₄)alkyl, O—(C₁₋₄)alkyl, CF₃,OCF₃ or NR²⁵R²⁶ (wherein R²⁵ and R²⁶ independently of one another denoteH, methyl or acetyl);

[0073] R⁴ denotes phenyl(C₁₋₄)alkyl or naphthyl(C₁₋₄)alkyl, whereinphenyl may be substituted by 1 to 3 substituents, wherein thesubstituents independently of one another denote halogen (F, Cl, Br, I),(C₁₋₄)alkyl, O—(C₁₋₄)alkyl, CF₃, OCF₃ or NR²⁷R²⁸ (wherein R²⁷ and R²⁸independently of one another denote H, methyl or acetyl); and

[0074] R⁵ denotes H, (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl, CH₂COOH, CH₂C(O)NH₂,OH or phenyl(C₁₋₄)alkyl.

[0075] Preferred compounds of general formula I are those wherein

[0076] Ar denotes unsubstituted or mono- or disubstituted phenyl, orunsubstituted naphthyl, or Ar is phenyl substituted by —O—CH₂—O— or—O—(CH₂)₂—O—;

[0077] R¹ and R² together with the N to which they are bound denote aring of the formula

[0078]  wherein

[0079] r is 2 or 3 and

[0080] s and t are 2;

[0081] R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are as hereinbefore defined;

[0082] R³ is H or (C₁₋₄)alkyl,

[0083] R⁴ denotes phenyl(C₁₋₄)alkyl or naphthyl(C₁₋₄)alkyl, whereinphenyl may be substituted by 1 or 2 substituents, wherein thesubstituents independently of one another are halogen (F, Cl, Br, I),(C₁₋₄)alkyl, O—(C₁₋₄)alkyl, CF₃ or OCF₃; and

[0084] R⁵ denotes H, (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl, OH or(C₁₋₄)alkylphenyl.

[0085] Particular mention should be made of compounds of formula Iwherein

[0086] Ar is unsubstituted or mono- or disubstituted phenyl, orunsubstituted naphthyl [wherein the substituents of the phenylindependently of one another are halogen (F, Cl, Br, I), methyl,methoxy, CF₃ or OCF₃] or Ar is phenyl substituted by —O—CH₂—O— or—O—(CH₂)₂—O—;

[0087] particularly those wherein Ar is phenyl, naphthyl, phenylsubstituted in position 3 and/or 4 by methoxy or halogen, or phenyl inwhich positions 2 and 3 or 3 and 4 are linked by —O—CH₂—O—, preferablythose compounds wherein

[0088] Ar is phenyl, phenyl substituted by methoxy in positions 3 and 4or phenyl wherein positions 3 and 4 or 2 and 3 are linked by —O—CH₂—O—.

[0089] Of the compounds defined above, special mention should be made ofthose wherein, in the ring

[0090] r is 2 or 3 and

[0091] R⁶ denotes

[0092] H,

[0093] (C₁₋₅)alkyl,

[0094] (C₃₋₅)alkenyl,

[0095] propynyl,

[0096] hydroxy(C₂₋₄)alkyl,

[0097] methoxy(C₂₋₄)alkyl,

[0098] di(C₁₋₃)alkylamino(C₂₋₄)alkyl,

[0099] amino(C₂₋₄)alkyl,

[0100] amino,

[0101] di(C₁₋₃)alkylamino,

[0102] monofluoro- to perfluoro(C₁₋₂)alkyl,

[0103] N-methylpiperidinyl,

[0104] pyridyl,

[0105] pyrimidinyl, or

[0106]  particularly those wherein

[0107] r is 3 and R⁶ is methyl;

[0108]  and those wherein

[0109] r is 2 and

[0110] R⁶ is

[0111] H,

[0112] (C₁₋₄)alkyl,

[0113] propenyl,

[0114] propynyl,

[0115] hydroxy(C₂₋₃)alkyl,

[0116] methoxyethyl,

[0117] di(C₁₋₂)alkylamino(C₂₋₃)alkyl,

[0118] aminoethyl,

[0119] amino,

[0120] dimethylamino,

[0121] CH₂CF₃,

[0122] N-methylpiperidinyl,

[0123] pyridyl,

[0124] pyrimidinyl, or

[0125]  preferably those wherein

[0126] r is 2 and

[0127] R⁶ is H, (C₁₋₃)alkyl, allyl, 2-propynyl, —CH₂CH₂OCH₃,—CH₂CH₂N(CH₃)₂, N-methylpiperidinyl, 2-pyrimidinyl or

[0128]  particularly those wherein

[0129] r is 2 and

[0130] R⁶ is H, CH₃, C₃H₇, CH(CH₃)₂, CH₂CH₂OH, CH₂CH₂OCH₃ orCH₂C₂N(CH₃)₂.

[0131] Of the compounds defined above, mention should also be made ofthose wherein

[0132] R¹ and R² together with the N to which they are bound form thering

[0133]  wherein

[0134] R⁸ is H and

[0135] R⁷ is OH

[0136]  wherein R¹⁶ and R¹⁷ independently of one another denote:

[0137] H

[0138] (C₁₋₃)alkyl,

[0139] (CH₂)_(n)OH wherein n is 2, 3 or 4 (CH₂)₂OCH₃

[0140] —(CH₂)_(n)Ph wherein n is 2 or 4 (CH₂)₂N(CH₃)₂

[0141]  particularly those wherein

[0142] R¹⁶ and R¹⁷ are both CH₃ or C₂H₅ or

[0143] R¹⁶ is H or CH₃ and R¹⁷ is

[0144] (C₁₋₃)alkyl,

[0145] (CH₂)₂OH,

[0146] (CH₂)₄OH or

[0147]  and those wherein

[0148] R⁷ denotes

[0149] N(CH₃)₂

[0150]  or

[0151]  especially those wherein

[0152] R¹ and R² together with the N to which they are bound form thering

[0153]  wherein

[0154]  (a)

[0155] R⁸ is H and

[0156] R⁷ is

[0157] wherein R¹⁶ and R¹⁷ both represent CH₃, C₂H_(5 l or CH) ₂CH₂OH orR¹⁶ is H or CH₃ and R¹⁷ is (C₁₋₃)alkyl,

[0158] (CH₂)₂OH or

[0159] (CH₂)₄OH or

[0160]  (b)

[0161] R⁸ is H and

[0162] R⁷ denotes

[0163] Of the compounds defined above, mention should also be made ofthose wherein

[0164] R¹ and R² together with the N to which they are bound form thering

[0165] Of the compounds defined above, special mention should also bemade of those wherein

[0166] R¹ and R² together with the N to which they are bound form thering

[0167]  wherein R¹¹ is H or (C₁₋₃)alkyl, particularly those wherein

[0168] R¹¹ is —CH(CH₃)₂.

[0169] Of the compounds defined above, the ones of particular interestare those wherein R³ is H; and/or

[0170] R⁴ denotes phenyl(C₁₋₄)alkyl, wherein phenyl may be substitutedby 1 or 2 substituents, wherein the substituents independently of oneanother denote halogen (F, Cl, Br, I), (C₁₋₄)alkyl, O—(C₁₋₄)alkyl, CF₃or OCF₃; and/or

[0171] R⁵ denotes H, (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl, —OH orphenyl(C₁₋₄)alkyl,

[0172] particularly those wherein

[0173] R⁴ denotes phenyl(C₂₋₄)alkyl, wherein the substituents are inpositions 3 and/or 5 of the phenyl ring and/or

[0174] R⁵ is H, methyl, OH or phenethyl,

[0175] preferably those wherein

[0176] and R⁵ is methyl.

[0177] Compounds of general formula I may have acid groups, chieflycarboxyl groups, and/or basic groups such as amino functions, forexample. Compounds of general formula I may therefore be present eitheras internal salts, as salts with pharmaceutically acceptable inorganicacids such as hydrochloric acid, sulphuric acid, phosphoric acid,sulphonic acid or organic acids (such as maleic acid, fumaric acid,citric acid, tartaric acid or acetic acid) or as salts withpharmaceutically acceptable bases such as alkali or alkaline earth metalhydroxides or carbonates, zinc or ammonium hydroxides or organic aminessuch as dimethylamine, triethylamine, triethanolamine, etc.

[0178] The compounds according to the invention may occur as racematesbut may also be obtained as pure enantiomers, i.e. in the (R)- or(S)-form.

[0179] The term naphthyl used hereinbefore includes both 1-naphthyl and2-naphthyl.

[0180] Test results for compounds according to the invention:

[0181] The receptor affinity for the NK₁-receptor (substance P-receptor)is determined on human lymphoblastoma cells (IM-9) with clonedNK₁-receptors, by measuring the displacement of ¹²⁵I-labelled substanceP. The K₁-values thus obtained show the efficacy of the compounds: Ki[nM] Example 1 1.2 Example 2 1.0 Example 3 19 Example 4 1.4 Example 51.5 Example 8 1.8 Example 9 2.5 Example 11 3.8 Example 12 5.0 Example 132.4 Example 15 0.98 Example 16 0.90 Example 17 7.75 Example 18 0.96Example 19 1.17 Example 20 2.0 Example 22 2.2 Example 23 2.5 Example 242.2 Example 25 6.0 Example 26 1.6 Example 28 1.3 Example 30 1.8 Example32 1.3 Example 33 7.4 Example 34 2.9 Example 47 1.7 Example 55 1.25Example 63 1.4 Example 64 1.1 Example 65 5.7 Example 73 2.0 Example 741.5 Example 75 0.44 Example 76 2.0

[0182] The compounds according to the invention are valuable neurokinin(tachykinin) antagonists which have both substance P antagonism and alsoneurokinin A and neurokinin B antagonistic properties. They are usefulfor the treatment and prevention of neurokinin-mediated diseases:

[0183] for the treatment or prevention of inflammatory and allergicdiseases of the respiratory tract, such as asthma, chronic bronchitis,hyperreactive respiratory tract, emphysema, rhinitis and cough,

[0184] and of the eyes, such as conjunctivitis and iritis,

[0185] of the skin, such as dermatitis in contact eczema, urticaria,psoriasis, sunburn, insect bites and stings, itching, sensitive orhypersensitive skin,

[0186] of the gastrointestinal tract, such as gastric and duodenalulcers, ulcerative colitis, Crohn's disease, irritable bowel andHirschsprung's disease,

[0187] of the joints, such as rheumatoid arthritis, reactive arthritisand Reiter syndrome;

[0188] for treating diseases of the central nervous system such asdementia, Alzheimer's disease, schizophrenia, psychoses, depression,headache (e.g. migraine or tension headaches), epilepsy, Parkinson'sdisease and stroke;

[0189] for treating herpes zoster and postherpetic pain, tumours,collagenoses, dysfunction of the deferent urinary tract, haemorrhoids,nausea and vomiting, caused for example by radiation or cytostatictherapy or motion and pain of all kinds.

[0190] The invention therefore also relates to the use of the compoundsaccording to the invention as therapeutic agents and pharmaceuticalpreparations which contain these compounds. They are preferably used inhumans. The compounds according to the invention may be administered byintravenous, subcutaneous, intramuscular, intraperitoneal or intranasalroute, by inhalation, by transdermal route, optionally aided byiontophoresis or enhancers known from the literature, and by oral route.

[0191] For parenteral administration the compounds of formula I or thephysiologically acceptable salts thereof, possibly with the conventionalsubstances such as solubilisers, emulsifiers or other adjuvants, aredissolved, suspended or emulsified. Solvents which may be used include:water, physiological saline solutions or alcohols, e.g. ethanol,propanediol or glycerol, sugar solutions such as glucose or mannitolsolutions or a mixture of several solvents.

[0192] In addition, the compounds may be administered by means ofimplants, e.g. of polylactide, polyglycolide or polyhydroxybutyric acidor intranasal preparations.

[0193] The oral efficacy of compounds of general formula I can bedemonstrated by the following standard test:

[0194] Inhibition of lowering of blood pressure caused by NK₁ inanaesthetised guinea pigs.

[0195] Guinea pigs weighing 300-500 grams were anaesthetised withpentobarbital (50 mg/kg i.p.), intubated and artificially ventilated.They were ventilated with 10 ml/kg of air at a frequency of 60 breathsper minute. The carotid artery was canulated and the arterial bloodpressure was recorded. A polyethylene tube was inserted-into the jugularvein for the intravenous supply of substances.

[0196] A temporary reduction in blood pressure was brought about atintervals of 10 minutes by intravenous administration of the NK₁-agonist[βAla⁴, Sar⁹, Met (O₂)¹¹]Sp(4-11)

[0197] in a dose of 0.2 μmol/kg. After the blood pressure thus producedhad been measured, the test compound was introduced into the duodenumand the NK₁-agonist was again injected every 10 minutes.

[0198] The results were expressed as a % inhibition of the reduction inblood pressure caused by the NK₁-agonist specified.

[0199] In a dosage of 1 mg/kg (administered into the duodenum) thecompound of Example 1 inhibited the lowering of blood pressure caused bythe NK₁-agonist by 80%.

[0200] The compounds according to the invention can be produced usinggenerally known methods.

[0201] The compounds may be prepared in various ways. The two mostcommon procedures are represented by the following diagram:

[0202] Method A. The carboxylic acid may be linked to the amine HN(R⁵)R⁴by various methods. Conventional methods are coupling processes such asthose used in peptide chemistry. A coupling reagent such as TBTU,DCCI/HOBt, CDI, etc., is added to the coupling partners in substantiallyequivalent quantities. Suitable solvents are DMF, THF, CH₂Cl₂, CHCl₃,acetonitrile or other inert solvents or mixtures thereof. The suitabletemperature range is between −50° C. and +120° C., preferably between 0°C. and 40° C.

[0203] The carboxylic acid may also initially be converted into thecorresponding acid halide by known methods using SOCl₂, SO₂Cl₂, PCl₃,PCl₅ or PBr₃ or mixtures thereof, and the acid halide is then reactedwith the amine HN(R⁵)R⁴ in an inert solvent such as CH₂Cl₂, THF ordioxane at temperatures between −50° C. and +100° C., typically at 0° to20° C.

[0204] Another alternative is to convert the carboxylic acid initiallyinto the alkylester, usually the methylester, by known methods and thisester is then reacted with the amine HN(R⁵)R⁴ in an inert solvent suchas DMF, dioxane or THF. The reaction temperatures are between 20° C. and150° C., typically between 50° C. and 120° C. The reaction may also becarried out in a pressurized container.

[0205] Method B. Here, the α-halo-arylacetamide derivative obtained byknown methods is reacted with the amine R¹(R²)NH, thereby cleavinghydrogen halide. Inorganic bases such as K₂CO₃, NaHCO₃ or CaCO₃ ororganic bases such as triethylamine, Hünig base, pyridine or DMAP areused to mop up the cleaved (or excess) hydrogen halide, or an excess ofthe amine R¹(R²)NH may be used. DMF, THF, dioxane or other inertsolvents are used. The temperature range for the reaction is from 0 to100° C., typically between 10 and 80° C.

[0206] Method C. The compounds according to the invention wherein R⁵ isnot H may also be prepared as follows: first of all, the correspondingcompound in which R⁵ is H is synthesised using method A or B. Then,N-alkylation is carried out as follows in order to introduce alkyl,cycloalkyl or CH₂COOH. The compounds according to the invention whereinR⁵ is H are deprotonated with an equivalent quantity of NaH, NaNH₂, KOH,NaOCH₃ or another strong base. Anhydrous inert solvents such as THF,dioxane or diethylether are used for this. Then the correspondingalkylating agent is added slowly in the form of the correspondinghalide, tosylate or mesylate. The reaction is carried out at atemperature within the range from −50° C. to +100° C., typically between0° C. and +50° C.

EXAMPLE 1

[0207]

[0208] Mp.: 105-115° C.

[0209] FAD-MS: (M+H)⁺=516.3.

[0210] 1st step: 0.71 q of 1-isopropylpiperazine were dissolved in 55 mlof anhydrous DMF, mixed with 0.64 g of Na₂CO₃, stirred for 20 minutes atRT and then cooled to 5° C. 1.15 g of methyl (R,S)-α-bromophenylacetatewere added and the suspension was stirred overnight at RT. Theprecipitate was filtered off and the filtrate was evaporated down. Theresidue was taken up in ethyl acetate, extracted twice with 10% KHCO₃solution and once with saturated NaCl solution. The organic phase wasdried over Na₂SO₄, filtered and evaporated down, to yield 1.23 g ofmethyl (R,S)-1-isopropyl-4-(2-phenylacetate)piperazine as a viscous oil.Yield: about 89%.

[0211] 2nd step: 1.23 g of the product from the 1st step were dissolvedin 10 ml of methanol and 10 ml of THF, mixed with 10 ml of 1N NaCH andthe mixture was stirred overnight at ambient temperature. The clearreaction solution was neutralised by the addition of 10 ml of 1N HCl,evaporated to dryness, the residue was treated with DMF and the solidwas separated by suction filtering. The filtrate was evaporated down andthe residue was triturated with ether, the solid substance removed bysuction filtering and dried in a desiccator. In this way, 1.1 g of(R,S)-1-i-propyl-4-(2-phenylacetic acid)piperazine were obtained as asolid white substance. Yield: 92%.

[0212] 3rd step: 0.37 g of the product of the 2nd step and 0.42 g ofN-methyl-3,5-bis-(trifluoromethyl)phenylethylamine were dissolved in 14ml of DMF and adjusted to pH 8.5 by the addition of about 0.4 ml of TEA.0.48 g of TBTU were added and the mixture was stirred overnight at roomtemperature. The clear reaction solution was evaporated down in vacuo,the residue was stirred with NaHCO₃ solution and extracted twice withethyl acetate. The combined organic phases were filtered and thefiltrate was evaporated down. The residue was chromatographed oversilica gel using CH₂Cl₂/MeOH (9:1) as eluant. The uniform fractionsobtained were evaporated down, dissolved in a little MeOH, acidifiedwith ethereal HCl and evaporated down again. The residue was trituratedwith ether and dried in a desiccator. 0.58 g of(R,S)-1-i-propyl-4-[2-phenylaceticacid-N-methyl-N-(3,5-bistrifluoromethylphenylethyl)]-amidedihydrochloride were obtained as a solid white substance. Yield: 75%.

[0213] The other compounds of the invention may be prepared analogously,e.g. the following:

EXAMPLE 2

[0214]

EXAMPLE 3

[0215]

EXAMPLE 4

[0216]

EXAMPLE 5

[0217]

EXAMPLE 6

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EXAMPLE 7

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EXAMPLE 8

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EXAMPLE 9

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EXAMPLE 11

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EXAMPLE 12

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EXAMPLE 13

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EXAMPLE 15

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EXAMPLE 16

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EXAMPLE 17

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EXAMPLE 19

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EXAMPLE 72

[0279]

EXAMPLE 73

[0280]

EXAMPLE 74

[0281]

EXAMPLE 75

[0282]

EXAMPLE 76

[0283]

[0284] Of these compounds, the compounds of Examples 1 and 8 arepreferred.

[0285] In the foregoing representations of the formulae, the CH₃ groupsare not drawn in full.

[0286] Compound 1, for example, contains a methyl group as the group R⁵.Pharmaceutical preparations Injectable solution 200 mg of activesubstance* 1.2 mg of monopotassium dihydrogen phosphate = KH₂PO₄ 0.2 mgof disodium hydrogen phosphate = {close oversize brace} (buffer)Na₂HPO₄.2H₂O 94 mg sodium chloride or {close oversize brace} (isotonicagents) 520 mg glucose 4 mg albumin (protease protection) q.s. sodiumhydroxide solution {close oversize brace} ad pH 6 q.s. hydrochloric acidad 10 ml water for injections Injectable solution 200 mg activesubstance* 94 mg sodium chloride or 520 mg glucose 4 mg albumin q.s.sodium hydroxide solution {close oversize brace} ad pH 9 q.s.hydrochloric acid ad 10 ml water for injections Lyophilisate 200 mg ofactive substance* 520 mg of mannitol (isotonic agent/framework agent) 4mg albumin Solvent 1 for lyophilisate 10 ml of water for injectionsSolvent 2 for lyophilisate 20 mg of Polysorbate ®80 = Tween ®80(surfactant) 10 ml of water for injections

1. Arylglycinamide derivatives of general formula I

or the pharmaceutically acceptable salts thereof, wherein Ar denotesunsubstituted or mono- to penta-substituted phenyl, or unsubstituted ormono- or disubstituted naphthyl [wherein the substituents of the phenyland naphthyl independently of one another denote halogen (F, Cl, Br, I),(C₁₋₄)alkyl, O—(C₁₋₄)alkyl, CF₃, OCF₃ or NR¹²R¹³ (wherein R¹² and R¹³independently of one another denote H, methyl or acetyl)] or Ar isphenyl substituted by —O—CH₂—O— or —O—(CH₂)₂—O—; R¹ and R² together withthe N to which they are bound denote a ring of the formula

 wherein r, s and t are 2 or 3; R⁶ denotes H, (C₁₋₅)alkyl,(C₃₋₅)alkenyl, propynyl, hydroxy(C₂₋₄)alkyl, methoxy(C₂₋₄)alkyl,di(C₁₋₃)alkylamino(C₂₋₄)alkyl, amino(C₂₋₄)alkyl, amino,di(C₁₋₃)alkylamino, monofluoro- to perfluoro(C₁₋₂)alkyl,N-methylpiperidinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or thegroup —CH₂—C(O)NR¹⁴R¹⁵,  wherein R¹⁴ is H or (C₁₋₄)alkyl and R¹⁵ is H,(C₁₋₄)alkyl, (C₃₋₆)cycloalkyl, hydroxy(C₂₋₄)alkyl, alkoxy(C₂₋₃)alkyl,phenyl(C₁₋₄)alkyl, or R¹⁴ and R¹⁵ together with the N to which they arebound form a ring (1-pyrrolidinyl, piperidino, morpholino or1-methylpiperazin-4-yl); R⁷ has one of the definitions (a) to (d), (a)hydroxy (b) 4-piperidinopiperidyl,

 wherein R¹⁶ and R¹⁷ independently of one another denote H, (C₁₋₄)alkyl,(C₃₋₆)cycloalkyl, hydroxy(C₂₋₄)alkyl, (C₁₋₃)alkoxy(C₂₋₄)alkyl,phenyl(C₁₋₄)alkyl or di(C₁₋₃)alkylamino(C₂₋₄)alkyl, or if R¹⁶ is H or(C₁₋₄)alkyl, R¹⁷ may also be —CH₂C(O)NR¹⁸R¹⁹, wherein R¹⁸ and R¹⁹ aredefined as R¹⁴ and R¹⁵ hereinbefore;

 wherein R²⁰ denotes H, (C₁₋₄)alkyl, (C₄₋₆)cycloalkyl or—CH₂C(O)NR²¹R²², wherein R²¹ and R²² are defined as R¹⁴ and R¹⁵hereinbefore; R⁸ is H R⁹ and R¹⁰ independently of each other denote(C₁₋₄)alkyl; R¹¹ denotes H, (C₁₋₅)alkyl, (C₃₋₅)alkenyl, propynyl,hydroxy(C₂₋₄)alkyl, methoxy(C₂₋₃)alkyl, di(C₁₋₃)alkylamino(C₂₋₃)alkyl,amino(C₂₋₃)alkyl, amino, di(C₁₋₃)alkylamino, monofluoro- toperfluoro(C₁₋₂)alkyl, N-methylpiperidinyl, pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl or the group —CH₂—C(O)NR²³R²⁴, wherein R²³ andR²⁴ are defined as R¹⁴ and R¹⁵ hereinbefore; R³ denotes H, (C₁₋₄)alkyl,unsubstituted or mono- to trisubstituted phenyl, wherein thesubstituents independently of one another denote halogen (F, Cl, Br, I),(C₁₋₄)alkyl, O—(C₁₋₄)alkyl, CF₃, OCF₃ or NR²⁵R²⁶ (wherein R²⁵ and R²⁶independently of one another denote H, methyl or acetyl); R⁴ denotesphenyl(C₁₋₄)alkyl or naphthyl(C₁₋₄)alkyl, wherein phenyl may besubstituted by 1 to 3 substituents, wherein the substituentsindependently of one another denote halogen (F, Cl, Br, I), (C₁₋₄)alkyl,O—(C₁₋₄)alkyl, CF₃, OCF₃ or NR²⁷R²⁸ (wherein R²⁷ and R²⁸ independentlyof one another denote H, methyl or acetyl); and R⁵ denotes H,(C₁₋₄)alkyl, (C₃₋₆)cycloalkyl, CH₂COOH, CH₂C(O)NH₂, OH orphenyl(C₁₋₄)alkyl.
 2. Compound according to claim 1 wherein Ar denotesunsubstituted or mono- or disubstituted phenyl, or unsubstitutednaphthyl, or Ar is phenyl substituted by —O—CH₂—O— or —O—(CH₂)₂—O—; R¹and R² together with the N to which they are bound denote a ring of theformula

 wherein r is 2 or 3 and s and t are 2; R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ aredefined as in claim 1; R³ is H or (C₁₋₄)alkyl, R⁴ denotesphenyl(C₁₋₄)alkyl or naphthyl(C₁₋₄)alkyl, wherein phenyl may besubstituted by 1 or 2 substituents, wherein the substituentsindependently of one another are halogen (F, Cl, Br, I), (C₁₋₄)alkyl,O—(C₁₋₄)alkyl, CF₃ or OCF₃; and R⁵ denotes H, (C₁₋₄)alkyl,(C₃₋₆)cycloalkyl, OH or phenyl(C₁₋₄)alkyl.
 3. Compound according toclaim 1 or 2, wherein Ar is unsubstituted or mono- or disubstitutedphenyl, or unsubstituted naphthyl [wherein the substituents of thephenyl independently on one another denote halogen (F, Cl, Br, I),methyl, methoxy, CF₃ or OCF₃] or Ar is phenyl substituted by —O—CH₂—O—or —O—(CH₂)₂—O—.
 4. Compound according to claim 3, wherein Ar is phenyl,naphthyl, phenyl substituted by methoxy or halogen in position 3 and/or4 or phenyl wherein positions 2 and 3 or 3 and 4 are linked by—O—CH₂—O—.
 5. Compound according to claim 4, wherein Ar is phenyl,phenyl substituted by methoxy in positions 3 and 4 or phenyl in whichpositions 3 and 4 or 2 and 3 are linked by —O—CH₂—O—.
 6. Compoundaccording to one of claims 1 to 5, wherein in the ring

r is 2 or 3 and R⁶ denotes H, (C₁₋₅)alkyl, (C₃₋₅ )alkenyl, propynyl,hydroxy(C₂₋₄)alkyl methoxy(C₂₋₄)alkyl, di(C₁₋₃)alkylamino(C₂₋₄)alkyl,amino(C₂₋₄)alkyl, amino, di(C₁₋₃)alkylamino, monofluoro- toperfluoro(C₁₋₂)alkyl, N-methylpiperidinyl, pyridyl, pyrimidinyl, or


7. Compound according to claim 6, wherein r is 3 and R⁶ is methyl. 8.Compound according to claim 6, wherein r is 2 and R⁶ is H, (C₁₋₄)alkyl,propenyl, propynyl, hydroxy(C₂₋₃)alkyl, methoxyethyl,di(C₁₋₂)alkylamino(C₂₋₃)alkyl, aminoethyl, amino, dimethylamino, CH₂CF₃,N-methylpiperidinyl, pyridyl, pyrimidinyl or


9. Compound according to claim 8, wherein r is 2 and R⁶ is H,(C₁₋₃)alkyl, allyl, 2-propynyl, —CH₂CH₂OCH₃, —CH₂CH₂N(CH₃)₂,N-methylpiperidinyl, 2-pyrimidinyl or


10. Compound according to claim 9, wherein r is 2 and R⁶ is H, CH₃,C₃H₇, CH(CH₃)₂, CH₂CH₂OH, CH₂CH₂OCH₃ or CH₂CH₂N(CH₃)₂.
 11. Compoundaccording to one of claims 1 to 5, wherein R¹ and R² together with the Nto which they are bound form the ring

 wherein R⁸ is H and R⁷ is OH

 wherein R¹⁶ and R¹⁷ independently of one another denote: H (C₁₋₃)alkyl,

(CH₂)_(n)OH wherein n is 2, 3 or 4 (CH₂)₂OCH₃ —(CH₂)_(n)Ph wherein n is2 or 4 (CH₂)₂N(CH₃)₂


12. Compound according to claim 11, wherein R¹⁶ and R¹⁷ are both CH₃ orC₂H₅ or R¹⁶ is H or CH₃ and R¹⁷ is (C₁₋₃)alkyl,


13. Compound according to claim 11 wherein R⁷ denotes


14. Compound according to claim 11, wherein R¹ and R² together with theN to which they are bound form the ring

 wherein (a) R⁸ is H and R⁷ is

 wherein R¹⁶ and R¹⁷ both represent CH₃, C₂H₅ or CH₂CH₂OH or R¹⁶ is H orCH₃ and R¹⁷ is (C₁₋₃)alkyl,

(CH₂)₂OH or (CH₂)₄OH or (b) R⁸ is H and R⁷ denotes


15. Compound according to one of claims 1 to 5, wherein R¹ and R²together with the N to which they are bound form the ring


16. Compound according to one of claims 1 to 5, wherein R¹ and R²together with the N to which they are bound form the ring

wherein R¹¹ is H or (C₁₋₃)alkyl.
 17. Compound according to claim 16,wherein R¹¹ is —CH(CH₃)₂.
 18. Compound according to one of claims 1 to17, wherein R³ is H.
 19. Compound according to one of claims 1 to 18,wherein R⁴ denotes phenyl(C₁₋₄)alkyl, wherein phenyl may be substitutedby 1 or 2 substituents, in which the substituents independently of oneanother are halogen (F, Cl, Br, I), (C₁₋₄)alkyl, O—(C₁₋₄)alkyl, CF₃ orOCF₃; and R⁵ denotes H, (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl, —OH orphenyl(C₁₋₄)alkyl.
 20. Compound according to claim 19, wherein R⁴denotes phenyl(C₂₋₄)alkyl, wherein the substituents are in positions 3and/or 5 of the phenyl ring and R⁵ is H, methyl, OH or phenethyl. 21.Compound according to claim 20, wherein R⁴ is

and R⁵ is methyl.
 22. Process for preparing a compound of generalformula I according to one of claims 1 to 21, characterised in that a)an acid

 or a halide or alkylester thereof is reacted with an amine

b) an α-haloarylacetamide

 is reacted with an amine

c) a compound I wherein R⁵ is H is N-alkylated; and a compound thusobtained is isolated as a free compound or as a pharmaceuticallyacceptable salt thereof.
 23. Pharmaceutical preparation containing acompound according to one of claims 1 to 21 and pharmaceuticallyacceptable carriers and excipients.
 24. Use of a compound according toone of claims 1 to 22 for preparing a pharmaceutical preparation for thetreatment and prevention of neurokinin-mediated diseases.
 25. Use of acompound according to one of claims 1 to 22 for the treatment andprevention of neurokinin-mediated diseases.